Emphysema is a major medical problem in the US and worldwide. Diagnostic methods for the evaluation of emphysema should be sensitive to regional lung structure at the alveolar level. Diffusion MRI with hyperpolarized 3He gas that evaluates the 3He-gas ADC (apparent diffusion coefficient) can provide this sensitivity. It offers information on lung microstructure and function not provided by traditional imaging modalities and pulmonary function tests. With 3He diffusion MRI, alveolar size and the integrity of alveolar walls can be evaluated, even though the alveoli are too small to be resolved by direct imaging. This points to the large potential for clinical application of ADC measurements with hyperpolarized 3He gas. However, until recently it was not clear what specific features of lung structure are probed by 3He gas ADC measurements. Recently we proposed a theoretical model based on a large body of histology data that provides this explanation. However, substantial questions must be answered if we are to understand the 3He ADC measurement and optimally exploit its diagnostic potential. In this proposal we will extend our mathematical model that relates anisotropic ADC measurements in lung to lung microstructural parameters. The mathematical model is based on a realistic structure of lung at the acinar level described in terms of acinar airways covered with alveolar sleeves. The theory of gas diffusion in lung is based on our key concept of anisotropic diffusion in lung acinar airways. We will conduct sophisticated multi-dimensional MR experiments on sacrificed mice with healthy lungs to test the fundamental feature of our mathematical model, the anisotropy of ADC. We will develop further and test our new diffusion 3He MRI technique for tomographic "lung biopsy" on a canine model of emphysema with physiology similar to human and establish a quantitative relationship between the severity of emphysema as determined by CT and the 3He anisotropic diffusivities. We will use 3He diffusion and ventilation MRI together with CT to study normal human subjects and patients with emphysema. Inter-comparison of these three techniques will establish quantitative relationships between CT, lung ventilation and anisotropic ADC measurements and will open up possibilities for new interpretations of results obtained by each modality. The potential implications are significant. A comprehensive clinical picture of emphysema progression, from initial onset of the alveolar deformation to the final stage, characterized by dramatic loss of lung function, will be established. New methods will be sensitive enough to allow early diagnosis of emphysema that will improve patient treatment.